EA010128B1 - 8-hydroxy-5-[(-hydroxy-2-[[(1r)-2-(4-methoxyphenyl)-1-methylethyl] amino][ethyl]-2(1h)-quinolinone monohydrochloride in crystalline form and the process for its preparation - Google Patents

Abstract

The invention relates to 8-hydroxy-5- [(1R)-1-hydroxy-2[[(1R)-2-(4-methoxyphenyl)-1-methyl ethyl] amino] ethyl] -2 (1H)-quinolinone monohydrochloride of formula (I) in crystalline form, provided with suitable characteristics in order to be used for the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or vehicles and the process for its preparation.

Description

The present invention relates to 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2 (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone monohydrochloride formulas (I)

OH (I) in crystalline form. The present invention also relates to a method for isolating compound (I) by crystallization and its use for the manufacture of pharmaceutical compositions for inhalation in combination with suitable carriers or excipients.

Field of Invention

8-Hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) quinolinone monohydrochloride is known from the European patent No. EP 0147719 as a bronchodilator having an effective stimulating effect on the beta-2 adrenoceptor.

Additionally, the authors of the present invention created a compound under the experimental code CHE 4225, which was also defined as 8-hydroxy-5 - {(1K) -1-hydroxy-2- [S - [(1K.) - 2 (parametoxyphenyl) -1 -methylethyl] amino] ethyl} carbostyril hydrochloride and is called TA 2005.

State of the art

A method for producing TA 2005 is described in EP 0147719, Example 4. Specifically, a method for isolating a crude product is presented in step (3-a), where insoluble substances obtained after catalytic hydrogenation of 3.5 g of 8-benzyloxy-5 - {(1K) - 1-hydroxy-2- [L - ((1K) -2- (paramethoxyphenyl) -1methylethyl) amino] ethyl} carbostyril hydrochloride in tetrahydrofuran (100 ml) and water (10 ml), collected by filtration and washed with aqueous 10% ethanol solution. The filtrate and washes were combined, and the combined solution was concentrated under reduced pressure to remove the solvent. The residue was crystallized with a mixture of ethanol, water and isopropyl ether, and the crystalline precipitates were collected by filtration. 2.38 g of 8-hydroxy-5 - {(1K) -1-hydroxy-2- [L - [(1K.) - 2- (paramethoxyphenyl) -1methylethyl] amino] ethyl} carbostyril hydrochloride are obtained in the form of colorless crystals.

The yield was 83%, and the final product showed the following characteristics:

Mp: 170.0-171.5 ° C (decomp.) [A] _s ²² -64.40 ° (s = 1.00, methanol)

IR _umax ^P401 (cm ^-1 ): 3300 (wide), 1640, 1610, 1600.

Object of the invention

This invention relates to monohydrochloride 8-hydroxy-5 - [(1K.) - 1-hydroxy-2 - [[(1K.) - 2- (4methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) - quinolinone in crystalline form having suitable characteristics for the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or excipients.

For the sake of brevity, this compound will also be determined by code CHE 4226.

The compound of the invention is preferably administered by inhalation.

Inhalation preparations where the active compound is in solid form include powder compositions that are to be delivered with a powder inhaler (ΌΡΙ, bgu ro \\ '6cg sya1eg), aerosol compositions containing a suspension of the drug particles in a gas propellant to be delivered by metered-dose inhaler under pressure (ρΜΌΙ, rhekkigί / eb si1e6e6-6o5e si1eg), and aerosol formulations in the form of aqueous suspensions, to be delivered by nebulizer.

The effectiveness of this route of administration may be limited by the difficulties encountered in creating suitable and similar dosages available to the lungs.

One of the most important characteristics is to ensure a uniform distribution of the active compound in the preparation, especially when it is potent and should be given in low doses.

In addition, the solid compound in the composition should be as pure as possible and should have the required chemical and physical stability.

In addition, in the formulations for inhalation, the active compound in the solid state must be present in the form of fine particles of a controlled size that does not exceed a mass median diameter (ΜΜΌ, tag 8 teFap Fatel) of approximately 10 μm, preferably 6 μm, more preferably 5 μm, to achieve maximum penetration into the lungs.

- 1 010128

These particles are traditionally obtained by techniques such as micronization or grinding.

Such techniques may produce particles that have regions with a partially amorphous structure and tend to change structure when stored under various environmental conditions, and / or are processed to produce pharmaceutical compositions.

Therefore, the particles of the active compound must have an adequate degree of crystallinity in order to be highly stable during the grinding or micronization process and sufficiently stable for subsequent pharmaceutical use.

Thus, an object of the present invention is to provide a stable crystalline monohydrochloride of 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl ] -2 (1 N) -quinolinone.

Another objective of the invention is to propose a method for producing this compound with an adequate degree of crystallinity. The compound of the invention is chemically and physically stable and maintains the same degree of crystallinity as after being subjected to micronization or grinding processes.

In the prior art, to obtain 8-hydroxy-5 - {(1K.) - 1-hydroxy-2- [S - ((1K.) - 2 (paramethoxyphenyl) -1-methylethyl) amino] ethyl} carbostyril hydrochloride, after collecting the crude product and washing with an aqueous 10% ethanol solution, the filtrate and washing were combined, and the combined solution was concentrated under reduced pressure to remove the solvent, the residue was crystallized with a mixture of ethanol, water and isopropyl ether, and the crystalline precipitates were collected by filtration, but there were no indications about how to carry out the process of krista lizization.

It has now been found that in said crystallization method, where the residue obtained after solvent removal is dissolved by heating an ethanol-water mixture (95: 5), and the solution is concentrated under reduced pressure to remove part of the solvent, the volume to which the solution volume is reduced , is critical. In fact, it was found that the solution should be concentrated to a volume equal to or greater than 1/3 of its original volume. In addition, isopropyl ether must be added to the concentrated solution slowly, for at least 5 minutes and at a higher temperature than 30 ° C.

The above conditions make it possible to obtain a homogeneous solution in which uniform and regular crystal growth takes place.

In fact, it was found that if the volume of the crude product concentrate is too small and, in particular, less than 1/3 of its original volume, and the addition of isopropyl ether is carried out too quickly, for example, within less than 5 minutes, a highly concentrated crude compound precipitates quickly, thick, unfiltered suspensions, the compound includes high levels of mother liquors, consisting of solvents and impurities dissolved in them, and it can be distinguished with great difficulty. In addition, during isolation and drying, it includes a significant amount of impurities.

Moreover, a high percentage of the compound is in an amorphous state and, as previously emphasized, particles of an amorphous structure can cause many problems when they are included in inhalation preparations: in fact, this species of particles is extremely prone to cohesion, tends to stick together friend and the tendency to absorb ambient moisture on its surface over time.

Thus, there is a need for a compound with an adequate degree of purity and an adequate degree of crystallinity.

The present invention provides SNT 4226 in pure crystalline form and a process for its preparation.

In order to obtain the crystalline compound of the invention, crude 8-hydroxy-5 - [(1K.) - 1-hydroxy-2 - [[(1K.) - 2 (4-methoxyphenyl) -1-methylethyl ] amino] ethyl] -2 (1H) -quinolinone, which was obtained, for example, according to the method disclosed in EP 0147719, by crystallization from a mixture of ethanol, water and isopropyl ether.

A suitable recrystallization solvent is a protic solvent, such as ethanol, isopropanol or aqueous mixtures thereof. A preferred solvent is an ethanol-water mixture.

The most suitable solvent for recrystallization is an ethanol-water mixture in a ratio of 97: 3 to 95: 5 vol / vol. Advantageously, after dissolving the crude compound in the aforementioned solvent and prior to isolating the final product, an intermediate step is carried out to distill the aqueous ethanol solution under reduced pressure to remove residual isopropyl ether from the mixture, as well as to improve the yield.

Preferably, the distillation process is continued until the volume of the solution decreases to a volume of 1/2 to 1/3 of the original volume.

The recrystallization method according to the invention makes it possible to effectively remove

- 2010128 contaminants up to levels equal to or lower than 0.5%, preferably 0.2%, even more preferably 0.1%, in order to obtain a compound in pure crystalline form having suitable characteristics for its use in the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or excipients.

DETAILED DESCRIPTION OF THE INVENTION

The method according to EP 0147719, which is in its entirety included in the present invention, includes filtering and washing with aqueous ethanol the suspension obtained after the catalytic hydrogenation of 8-benzyloxy-5 - {(1K) -1-hydroxy-2- [S - ((1K ) -2- (paramethoxyphenyl) -1-methylethyl) amino] ethyl} carbostyril hydrochloride, to remove the catalyst. The solution was concentrated under reduced pressure to remove the solvent. According to the present invention, the residue obtained after removal of the solvent is dissolved by heating in an ethanol-aqueous mixture in a preferred ratio of 95: 5, and the solution obtained in this way is concentrated under reduced pressure, preferably from 200 to 400 mbar (20 to 40 kPa) , at a temperature of from 30 to 55 ° C, preferably at a temperature of from 45 to 50 ° C, to a volume of from 1/2 to 1/3 of the original volume. Then, diisopropyl ether is slowly added to the warm solution with stirring. The addition of diisopropyl ether is carried out for at least 5 minutes, preferably for more than 10 minutes, and more preferably for a period of from 20 to 30 minutes.

The mixture was then cooled with stirring at a temperature of 0 to 10 ° C. for 1-2 hours, and the solid was isolated and washed with ethanol.

The wet crude product is suspended in ethanol, refluxed at 75-78 ° C and slowly added with water until a clear solution is obtained. This solution is filtered and the filter washed with ethanol. The warm solution is concentrated under stirring under reduced pressure at a temperature not lower than 40 ° C, preferably from 40 to 50 ° C, more preferably from 45 to 48 ° C, to a volume in the range from about 1/2 to about 1/3 of its original volume. The product begins to crystallize from the solution, giving a suspension. The suspension is slowly cooled and kept at a temperature of from about 0 to 10 ° C, preferably from about 0 to 5 ° C, for at least 1 hour and up to 20 hours or more with stirring. The solid is isolated by filtration, washed with ethanol and finally dried in the traditional way, for example, by air drying, drying under reduced pressure or drying in the presence of a sterile inert gas to obtain a crystalline compound.

8-hydroxy-5 - [(1B) -1-hydroxy-2 - [[(1B) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone monohydrochloride, which can be obtain using the method described above, investigated to determine the melting temperature by differential scanning calorimetry (E8C), the specific value of the optical rotation [a] _with ²⁰ , enantiomeric purity by capillary zone electrophoresis and high performance liquid chromatography (HPLC), the amount of total impurities by HPLC and powder x-ray diffraction (CKP) patterns.

8-hydroxy-5 - [(1B) -1-hydroxy-2 - [[(1B) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone monohydrochloride according to the present invention characterized by a melting point in the range of 180-200 ° C (with decomposition), preferably 185-195 ° C (with decomposition), more preferably 190-195 ° C (with decomposition), which was determined by the E8C method with a scanning speed of 10 ° C / min ;

the specific value of the optical rotation [a] _with ²⁰ (c = 1.00, methanol) = -68.0 °;

enantiomeric purity greater than 99.0%, preferably greater than 99.5%, as determined by capillary zone electrophoresis and HPLC;

impurity levels of less than 0.5%, preferably less than 0.2%, even more preferably less than 0.1%, which are determined by the HPLC method;

an X-ray diffraction pattern identical or substantially identical to the pattern presented after the example below. Accordingly, this compound has, among others, one or more of the following characteristic peaks of CKE: 12.2; 13.6; 16.3; 18.0; 18.2; 19.2; 21.4; 21.9; 22.8; 23.5; 24.2; 24.9; 26.6; 28.5; 29.4; 29.9 and 33.9 ± 0.2 ° / 2 theta;

the degree of crystallinity, expressed in wt.% of the crystalline compound relative to the total mass of the compound, is at least 90%, preferably at least 93%, even more preferably at least 95%, which is determined by the microcalorimetric method according to our own development of the inventors.

The following example illustrates the present invention.

Example.

Crystallization of monohydrochloride 8-hydroxy-5 - [(1B) -1-hydroxy-2 - [[(1B) -2- (4-methoxyphenyl) -1methylethyl] amino] ethyl] -2 (1H) -quinolinone (CHE 4226 monohydrochloride )

In order to obtain crystalline CHE 4226 according to the present invention, the residue obtained, for example, after the catalytic hydrogenation of 8-benzyloxy-5 - {(1B) -1-hydroxy-2 [P - [(1B) -2- (paramethoxyphenyl) -1-methylethyl] amino] ethyl} carbostyryl hydrochloride (100 g) as described in Step 3 of Example 4 of EP 0147719 was dissolved in approximately 1300 ml of ethanol and 100 ml of water and concentrated in a rotary evaporator ( bath temperature = 55 ° C; vacuum = -0.8 bar (-80 kPa)) until the residual volume reaches about 600 ml. Isopropyl ether (560 ml) was added dropwise to a warm solution (T = 45-50 ° C) over 30 minutes. The mixture was cooled at 5-10 ° C and stirred for 60 minutes until the crystallization process was completed, then it was filtered on a Buckner filter (Wiskpeg), washing the solid with 200 ml of ethanol.

Wet crude monohydrochloride 8-hydroxy-5 - [(1B) -1-hydroxy-2 - [[(1B) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone ( 154.6 g; corresponding to 73 g if it was dried at 60 ° C under vacuum) suspended in ethanol (580 ml) and the suspension was heated at 78 ° C under reflux; 25 ml of water was slowly added dropwise until a clear solution was obtained. The hot solution was filtered on a Buckner filter, washing with 150 ml of ethanol. The filtered solution was concentrated in vacuo (bath temperature = 55-65 ° C; vacuum = 250-300 mbar (25-30 kPa); solution temperature = 45-48 ° C), distilling approximately 360 ml of solvent. The vacuum was disconnected and 390 ml of ethanol was added to the residual suspension, stirring at 45 ° C. until a homogeneous suspension was obtained. The suspension was cooled at a temperature of less than 5 ° C for 90 minutes, then it was kept at 5 ° C for 20 hours. The suspension was filtered on a Buckner filter, washing with 150 ml of ethanol. The solid was then dried under vacuum at 60 ° C for 24 hours. 58.4 g of 8-hydroxy-5 - [(1K.) - 1-hydroxy-2 - [[(1B) -2- (4-) monohydrochloride were obtained methoxyphenyl) -1methylethyl] amino] ethyl] -2 (1H) -quinolinone (yield 80.0%) having the following characteristics:

melting point in the range of 190-194 ° C (decomposition), which is determined by the I8C method with a scanning speed of 10 ° C / min;

specific optical rotation value [α] _Β ²⁰ (c = 1.00, methanol) = -68.0 °;

enantiomeric purity above 99.5%, which is determined by capillary zone electrophoresis;

total impurities less than 0.1%;

powder X-ray diffraction (XCE) pattern shown in the drawing and represented by the following main peaks:

Angle [72 Θ] 12.3 13.6 16,4 18.0 18,4 19.3 21,4 21.9 22.9 23.6 24.3 25.0 26.7 28.6 29.5 29.9 34.0

Rel Intensity [%] 21.0 54,2 64.9 37.5 44.5 50.1 55.8 100.0 35.6 36.9 88.4 21,4 32,5 22.6 30.5 14.8 20,4

The degree of crystallinity of the compound was determined according to the method of differential scanning calorimetry (I8C), developed by the authors of this patent, based on the measurement of heat of fusion.

According to the specified method, a scanning speed of 130 ° C./min is used to estimate the percentage of crystalline compound in the sample by determining the ratio of AN (heat of fusion) of the sample relative to AN of a 100% crystalline reference standard determined in the same temperature range and in the same experimental conditions . A 100% crystalline reference standard was obtained by suspending the compound in ethanol, then filtering to remove residual amorphous compound dissolved in ethanol and drying.

This method was applied to samples of the compounds of the example as such, and after grinding or micronization. All samples showed a degree of crystallinity higher than 90%, which was also maintained after the compound was subjected to grinding and micronization processes.

Claims (6)

CLAIM 1. Monohydrochloride 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone, characterized by a melting point in the range of 180-200 ° C., which is determined by differential scanning calorimetry, a powder X-ray diffraction pattern having, among others, one or more of the following characteristic peaks: 12.2; 13.6; 16.3; 18.0; 18.2; 19.2; 21.4; 21.9; 22.8; 23.5; 24.2; 24.9; 26.6; 28.5; 29.4; 29.9 and 33.9 ± 0.2 ° / 2 theta, and the degree of crystallinity, expressed in wt.% Crystalline compound relative to the total mass of the compound, at least 90%. 2. Monohydrochloride of 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone claim 1, characterized by a melting point within 185195 ° C, which is determined by the method of differential scanning calorimetry. 3. 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone monohydrochloride according to 1 or 2, having a degree of crystallinity, expressed in wt.% crystalline compounds relative to the total mass of the compound, at least 93%. 4. Monohydrochloride of 8-hydroxy-5 - [(1K) -1-hydroxy-2 - [[(1K) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -quinolinone any one of claims 1 to 3, having a degree of crystallinity, expressed in wt.% crystalline compounds relative to the total mass of the compound, at least 95%. 5. A method of producing a compound according to any one of claims 1 to 4, comprising crystallizing or recrystallizing the compound from a water-ethanol solution with the addition of diisopropyl ether, where the water-ethanol solution is concentrated to a volume of 1/2 to 1/3 of the original volume and adding diisopropyl ether is carried out for at least 5 minutes 6. The method according to claim 5, further comprising the step of recrystallization from a protic solvent, including ethanol, isopropanol or their aqueous mixtures.